Significance of Localization of Coactivators in Tamoxifen Resistance.

摘要

Antiestrogens and selective estrogen receptor modulators such as tamoxifen are effective in controlling the progression of estrogen receptor (ER)-positive breast tumors to more invasive phenotypes. However, over time, many patients acquire resistance to tamoxifen. The mechanisms underlying tamoxifen resistance remain elusive. Proline-, glutamic acid , and leucine-rich protein-1 (PELP1) is a novel ER- coregulator that plays a role in both the genomic and extranuclear actions of ER in hormonally responsive tissues and in some breast tumors PELP1 was localized only in the cytoplasm. To understand the significance of the cytoplasmic localization of PELP1 in human breast tumors, we created model cells that was expressed PELP1 only in the cytoplasm (PELP1- cyto). We found that PELP1-cyto cells were hypersensitive to estrogen but resistant to tamoxifen. In addition, PELP1-cyto cells exhibited increased association of PELP1 with Src, enhanced MAPK activation, and constitutive activation of AKT. The altered localization of PELP1 was sufficient to trigger the interaction of PELP1 with the p85 subunit of phosphatidylinositol- 3- kinase (PI3K), leading to PI3K activation. In addition, PELP1 interacted with epidermal growth factor receptors and participated in growth factor mediated ER transactivation functions. Our results suggest that the altered localization of PELP1 modulates sensitivity of breast cancer cells to antiestrogens.